Erectile Dysfunction Flashcards
What is erectile dysfunction?
Persistent (at least 6 months) inability to achieve or maintain an erection of sufficient duration and firmness to complete satisfactory sexual intercourse
ED incidence increasing with ___
Age
around 50% of men 40yo and older experience ED
Describe the physiology of an erection
Flaccid state
- Arterial blood flow into penis = Venous blood flow out of penis
During erection
- Blood inflow > Blood flow out of penis
MOA of erection:
- Sexual arousal causes nerve to release chemicals that increase arterial flow into penis - Smooth muscle relaxes, corpora cavernosa fills up with blood, spongy muscle tissue relaxes and traps blood, makes penis firm
- Swelling causes compression of venules against tunica albuginea, which decreases venous outflow
What are the 2 systems that play a role in the physiology of an erection?
- Activated parasympathetic system
- Functional hormonal system
How does activation of parasympathetic system lead to an erection?
Sexual arousal causes acetylcholine release
- ACh increases Nitric Oxide (NO) which increases the activity of guanylate cyclase, and increases cyclic guanosine monophosphate (cGMP)
- ACh and Prostaglandins E increases adenyl cyclase, which increases cyclic adenosine monophosphate (cAMP)
cGMP and cAMP cause smooth muscle relaxation and vasodilation, hence increase blood flow
How does the functional hormonal system lead to an erection?
Testosterone encourages libido
Usual normal serum conc. of T: 300-1000ng/dL (10.4 - 38.2 nmol/L)
Describe the relationship between Testosterone levels and ED
Low testosterone does not mean ED
Normal testosterone can have ED
Hence, testosterone levels are only assessed in the perspective of presence of ED symptoms
Describe the physiology of Detumescence
(3 pathways)
- Deactivating of parasympathetic system
- cGMP deactivated by PDE-5 to 5-GMP (predominantly found in penis)
- stops the vasodilation and blood inflow - Activated sympathetic system
- induces smooth muscle contraction via a2 adrenergic receptors of arterioles resulting in a reduction of blood flow - Serotonin
- inhibitory effect on sexual arousal
- recall that a possible SE of SSRI is ED
What are the 4 etiology of ED?
- Organic ED (80%) - vascular, nervous, hormonal systems compromised, or medication induced
- Psychogenic ED - due to thoughts, feelings (e.g., malaise, loss of attraction, stress, performance anxiety, mental disorders, sedation)
- Mixed ED
- Others - social habits (smoking, alcohol, illicit drug use), obesity
Organic ED
Discuss the vascular causes of ED
Arteriosclerosis
Peripheral vascular disease
Hypertension
Diabetes (DM)
=> Associated with narrowed blood vessels, reduced inflow of blood to penis
Organic ED
Discuss the hormonal causes of ED
Hypogonadism - insufficient testosterone
Hyperprolactinemia - too much prolactin suppresses testosterone production
Organic ED
Discuss the nervous system causes of ED
Central: Spinal cord trauma or disorders, stroke, CNS tumors
Peripheral: Diabetes, Neuropathy, Urethral surgery
=> Associated with loss of sensation, nerve damage, nerve signals from brain or spinal cord do not reach penis
List examples of medication induced ED
A B C D 5 S
- Clonidine, Methyldopa, BB (except Nevibolol), Thiazide diuretics
- Anticholinergics (TCA, 1st gen antihistamines, phenothiazines)
- Dopamine antagonist (e.g., metoclopramide)
- Serotonin Selective Reuptake Inhibitors
- Finasteride, Dutasteride
- CNS depressants (e.g., Benzodiazepines, anticonvulsants)
- Clonidine, Methyldopa, BB (except Nevibolol), Thiazide diuretics
Explain MOA of ED, and alternatives
These are blood pressure (HTN) medications
MOA: Decrease penile blood flow
Alternatives: Nevibolol, ACEi, ARB, Loop diuretics
- Anticholinergics (TCA, 1st gen antihistamines, phenothiazines)
Explain MOA of ED, and alternatives
MOA: Anticholinergics decrease Acetylcholine activity, decrease parasympathetic activation
Alternatives: Bupropion, trazodone, 2nd gen antihistamines, 2nd gen atypical antipsychotics
- Dopamine antagonist (e.g., metoclopramide)
Explain MOA of ED, and alternatives
MOA: Dopamine causes sexual arousal and stimulation, hence antagonist reduces this
Alternatives: PPIs, erythromycin
- Serotonin Selective Reuptake Inhibitors
Explain MOA of ED, and alternatives
MOA: Increased serotonin in brain, serotonin has inhibitory effect on sexual arousal. Also decrease testosterone
Alternatives: Bupropion, Trazodone
- Finasteride, Dutasteride
Explain MOA of ED, and alternatives
MOA: decrease testosterone
Alternatives: (for BPH) Terazosin, Alfurosin
- CNS depressants (e.g., Benzodiazepines, anticonvulsants)
Explain MOA of ED, and alternatives
MOA: Suppress perception of psychic stimulus
Alternatives: Anticonvulsants (Valproic acid, Gabapentin) *less drowsy options
What are some complications of ED?
- Inability to achieve erection
- Loss of interest in sexual activities
- Depression
- Performance anxiety
- Embarrassment
- Angry
- Low self-esteem
- Disharmony in rsp
What are the parameters for evaluation of ED?
- Signs and symptoms
- SHIM score
- Workup to identify underlying causes of ED - medical, social, surgical history, lab results (BG, lipid, testosterone etc.)
- Evaluation for cardiovascular disease
Explain the Sexual Health Inventory for Men (SHIM) scoring system
Mild to no ED: 17-21 points
Moderate to severe: <11 points
*Lower points, severity increase
Why should CV evaluation be conducted in all patients with ED?
- ED might be an early symptom of unidentified comorbid CVD (think impaired blood flow to penis)
- As such, impt to evaluate as sexual activity activates the sympathetic system, incr BP and HR, may incr risk of myocardial infarction
=> If low risk of CVD: can engage in sexual activity
=> If unknown/not low risk: exercise stress test to evaluate exercise capacity
=> If unstable or severe symptomatic CVD: defer until condition stabilized
What can be done to reduce the risk of CV complications with sexual activity?
Cardiac rehabilitation and regular exercise
Management of ED
What is the first step in the management of ED, before non-pharmacologicals and pharmacologicals are used?
Recognise, reverse, and treat the underlying cause
E.g., vascular, nervous, hormonal, medication-induced, psychological (include loss of attraction)
Management of ED
What are some non-pharmacological methods?
- Address modifiable risk factors (smoking, weight, BG, BP, lipids, exercise, alcohol)
- Psychotherapy (counseling, performance anxiety)
- Devices: vacuum erection device (VEDs)
- Surgery: penile implant
Management of ED
What is the first line agent in the management of ED?
phosphodiesterase type 5 inhibitors (PDE5i)
Management of ED
What is the MOA of PDE5i?
MOA: inhibit the deactivation of cGMP by enzyme PDE5 to 5’GMP, which will increase cGMP, cause smooth muscle relaxation and vasodilation, increase blood flow to the corpora cavernosa, causing an erection
Management of ED
PDE5i causes an erection only after _______
After sexual stimulation
Management of ED
What is the failure rate of PDE5i
Failure rate 30-40% (similar across all agents in the class)
May need to try several times (5-6 times) to work, do not give up after one dose
Management of ED
What are the 4 agents in PDE5i class
Sildenafil
Vardenafil
Tadalafil
Avanafil
*They have similar efficacy, but diff onset, duration of action, and SE profile
Management of ED
Which of the 4 PDE5i agents has the longest duration of action and can be taken daily?
Tadalafil
- Duration of action of 36h
- Can take 2.5-5mg PO daily
- Can be taken up to 36h before intercourse (hence regardless of sexual activity)
*The rest are taken PRN only
Management of ED
What are the timings to take each PDE5i agent before sexual intercourse?
Also state their onset of action and duration of action.
Sildenafil - 50mg 1h before intercourse, onset: 15-60min, DOA: 4h
Vardenafil - 10mg 1h before intercourse, onset: 25-60min, DOA: 4h
Tadalafil - 5mg up to 36h before intercourse, onset: 15min-2h, DOA: 36h
Avanafil - 100mg 30min before intercourse, onset: 15-30min, DOA: 6h
Management of ED
Which of the 4 PDE5i agents must be taken on empty stomach?
Sildenafil and Vardenafil
*Tadalafil and Avanafil can be taken regardless of food
Management of ED
Which of the 4 PDE5i agents require hepatic and/or renal dosage adjustments?
Sildenafil - hepatic and renal
Vardenafil - hepatic
Tadalafil - hepatic and renal
Avanafil - nil
Management of ED
In what groups of patient should a lower dose of PDE5i be used?
- Patients >=65yo
- Those taking alpha blockers (*hypotension)
- Patients with renal failure (*PDE5i may be renally excreted)
- Patients taking CYP3A4 inhibitors (PDE5i is a CYP3A4 substrate)
E.g., of CYP3A4 inhibitors
- macrolides
- azoles
- grapefruit
- cimetidine
- ritonavir
- saquinavir
Management of ED
What are the side effects of PDE5i?
- SEs due to vasodilation: Headache, rhinitis, flushing, muscle and back pain, dizziness, hypotension, dyspepsia
- Prolong erection and priapism
- seek emergency department treatment if >4h - Sudden hearing loss, may present with tinnitus and dizziness (rare)
- seek medical attention - QTc prolongation
- Vardenafil - Muscle pain
- Tadalafil (PDE11 affinity) - Ocular problems
- Sildenafil and Vardenafil (PDE6 affinity in retina)
- Reversible color discrimination, blue green tinting, blur vision
- Sensitivity to light
- Nonarteritic Anterior Ischemic Optic Neuropathy (NAION)
Management of ED
Which PDE5i agent can cause QTc prolongation?
Vardenafil (QV)
Management of ED
Which PDE5i agent can cause muscle pain? (due to affinity for?)
Tadalafil (MT)
- due to PDE11 affinity
Management of ED
Which PDE5i agents can cause ocular problems? (due to affinity for?)
Sildenafil and Vardenafil (VOS)
- PDE6 affinity in retina
Management of ED
What is Nonarteritic Anterior Ischemic Optic Neuropathy (NAION), a possible ocular problem with Sildenafil or Vardenafil?
What are the risk factors for NAION?
NAION
- Blood flow to optic nerve is blocked
- Cause sudden decreased vision or vision loss
- Stop use and seek medical attention immediately
Risk factors:
- DM
- Smoking
- HTN
- CVD
- Dyslipidemia
- Age >50yo
Management of ED
What are the possible DDIs with PDE5i?
- Nitrates (e.g., sublinual GTN to prevent MI)
- Life-threatening hypotension
- Potentiate vasodilation effect of GTN via incr cGMP due to concomitant blockade of cGMP degradation - Antihypertensive (including alpha-1 blockers)
- Hypotenstion - Alcohol
- Hypotenstion - CYP3A4 inhibitors
- Incr serum concentration of PDE5i (require lower dose)
Management of ED
What are the timing administrations if patient is on PDE5i and Nitrates?
Sildenafil - avoid nitrates for 24h after administration of Sildenafil
Vardenafil - avoid nitrates for 24h after administration of Vardenafil
Tadalafil - avoid nitrates for 48h after administration of Tadalafil
Avanafil - avoid nitrates for 12h after administration of Avanafil
Management of ED
How to monitor efficacy of PDE5i?
If failure reported,
- Assess whether patient has tried 5-6 times
- Administration with food
- Timing and frequency of dosing
- Lack of sexual stimulation
- Titration to max dose
If all modifiable factors addressed,
- Treat with a different PDE5i
- Proceed with more invasive therapy (e.g., device, surgical implant)
Management of ED
What safety monitoring parameters should be monitored for PDE5i?
- BP (watch for hypotension)
- Side effects (esp life-threatening - priapism, hearing loss, vision loss, QTc prolongation)
- Drug interactions
Management of ED
Apart from efficacy and safety of PDE5i, what else should be monitored?
Changes in cardiac health status (evaluate CVD)
Management of ED
When is testosterone replacement indicated for patient with ED?
Indicated as 1st line for patient with ED and SYMPTOMATIC hypogonadism, as confirmed by decreased libido AND low serum T conc.
Management of ED
What is the normal serum testosterone range?
300-1100ng/dL (10.4-38.2nmol/L)
Management of ED
What are the side effects of Testosterone replacement?
Irritability
Aggressive behaviour
Undesirable hair growth
Incr BP
Hepatotoxicity
Dyslipidemia
Polycythemia (high conc. of RBC => risk of MI, stroke)
Prostatic hyperplasia (CI for prostate cancer)
Management of ED
What are the dosage forms of Testosterone replacement?
IM injection (most common in Sg)
Buccal
Patch
Topical gel
Body spray
Nasal spray
Oral tablet
Management of ED
What is the monitoring interval for Testosterone levels when on Testosterone replacement?
Monitor within 1-3 months after initiation, and at 6-12 month intervals
Discontinue if theres no improvement in the symptoms of ED after 3 months
Management of ED
Describe the MOA of Alprostadil
Alprostadil MOA: Prostaglandin E1 analog, that (along with acetylcholine) can stimulate adenyl cyclase and increase cAMP, hence inducing smooth muscle relaxation, blood flow into penis, erection
Management of ED
Describe the following for Alprostadil
- Onset
- Need for sexual stimulation
- DDIs
Onset: 5-10min (fast)
Do not require sexual stimulation to work
DDI: do not use with PDE5i
Management of ED
What are the two dosage forms of Alprostadil and their associated SEs
- Intraurethral Alprostadil
- Pain, warmth, burning sensation of urethral
- Voiding difficulties
- Bleeding, spotting
- Priapism
- Partners may experience vaginal burning or itching
- Intracavernosal Alprostadil [*preferred due to better efficacy] - inject into side of penis
- Higher risk of priapism, bleeding, hematoma, fibrosis
- Disadvantages: fear of needles, invasive, lack of spontaneity, complicated administration technique
Management of ED
What drug is not HSA approved, but can be used in other countries for the management of ED?
Yohimbine
- alpha-2 antagonist (deactivate sympathetic system, relax smooth muscles)
